Transdermal microneedle continuous monitoring system

ABSTRACT

Transdermal microneedles continuous monitoring system is provided. The continuous system monitoring includes a substrate, a microneedle unit, a signal processing unit and a power supply unit. The microneedle unit at least comprises a first microneedle set used as a working electrode and a second microneedle set used as a reference electrode, the first and second microneedle sets arranging on the substrate. Each microneedle set comprises at least a microneedle. The first microneedle set comprises at least a sheet having a through hole on which a barbule forms at the edge. One of the sheets provides the through hole from which the barbules at the edge of the other sheets go through, and the barbules are disposed separately.

RELATED APPLICATIONS

The present application is a Divisional Application of U.S. patentapplication Ser. No. 16/111,618, filed Aug. 24, 2018, which is aContinuation Application of U.S. patent application Ser. No. 14/265,234,filed Apr. 29, 2014, entitled TRANSDERMAL MICRONEEDLE CONTINUOUSMONITORING SYSTEM, by Juang-Tang Huang, which claims the benefit ofTaiwanese Patent Application Ser. No. 103103314, filed Jan. 28, 2014,the contents of which are hereby incorporated by reference in theirentirety.

FIELD OF THE INVENTION

The present invention relates to a transdermal sensor, especially to atransdermal sensor obtain physiologic data by measuring theconcentration of hypodermal target molecules.

DESCRIPTION OF THE RELATED ART

Tissue fluid is mainly contained in subcutaneous tissue and includesamino acids, sugars, fatty acids, coenzymes, hormones,neurotransmitters, salts and waste products from the cells. Moreover,the tissue fluid is also the major communication channel for cell andblood. The concentrations of the various components in the tissue fluidare useful for determining user's physiological conditions.

The medicine will be slowly released over a long period in tissue fluidwhen the patient takes or injects the medicine. The concentrationvariation of medicine in the tissue fluid is continually monitoredduring development of medicine and clinical experiment. Therefore, thetissue fluid is commonly sampled to further examine or analyze inmedical treatment of patient.

The commercially available physiological examination instrumentsgenerally withdraw tissue fluid by using a needle piercing throughstratum comeum. However, the patient may feel painful for this kind ofinvasive sampling way. Moreover, the patient may be infected bymicroorganism originally present on epidermis and entering the patientbody as the stratum comeum is pierced by a needle. Transdermal sensorwith array-arranged microneedles pricking through skin is developed towithdraw tissue fluid in painless and minimally-invasive way.

The array-arranged microneedles of a transdermal sensor can bemanufactured with standard semiconductor process such as photolithographprocess and etching process. U.S. Pat. No. 7,344,499 discloses a processfor manufacturing silicon microneedles. As can be seen from the secondparagraph of the twelve column of this patent, firstly a silicon waferwith a first patterned photoresist layer is prepared. Next, a throughhole is defined on the wafer by anisotropic etching. Afterward, achromium layer is coated on the wafer and a second patterned photoresistlayer is formed atop the through hole to function as circular etchingmask. Next, the wafer is then etched to form outer tapered wall for themicroneedles. However, the silicon-based microneedles are brittle andtend to break when the microneedles prick through user's skin.

Alternatively, hollow microneedles with resin barbules are proposed,where the barbules are drilled by laser processing. Firstly, sheet withbarbules is formed by extruding polyimide or polyether ether ketone, andthen the barbules are drilled by laser to form hollow microneedles.However, the microneedles have compact size such that the barbules mayhave ragged edge after extrusion. Moreover, it is difficult to form ahollow microneedle with off-axis through hole or central through holehaving uniform inner diameter by laser processing.

SUMMARY OF THE INVENTION

One object of the present invention is to provide a transdermalmicroneedles continuous monitoring system, where the monitoring systemhas microneedles made by punching or etching to have sufficientmechanical strength. The microneedle can be kept intact after themicroneedle pricks user's skin for sensing. The microneedle has suchstructure that the sensing polymer can be advantageously coated on innersurface of the tip of the microneedle. The sensing polymer can beprevented from falling as the microneedle pricks user's skin forsensing.

Accordingly, the present invention provides a transdermal microneedlescontinuous monitoring system is provided. The transdermal microneedlecontinuous monitoring system includes a substrate, a microneedle unit, asignal processing unit and a power supply unit. The microneedle unit atleast comprises a first microneedle set used as a working electrode anda second microneedle set used as a reference electrode, the first andsecond microneedle sets arranging on the substrate. Each microneedle setcomprises at least a microneedle. The first microneedle set comprises atleast a sheet having a through hole on which a barbule forms at theperipheral. One of the sheets provides the through hole from which thebarbules at the edge of the other sheets go through, and the barbulesare disposed separately.

Another object of the present invention is to provide a sensing devicefor interstitial fluid, where the sensing device has microneedle made bypunching or etching to have sufficient mechanical strength. Themicroneedle can be kept intact after the microneedle pricks user skinfor sensing. The microneedle has such structure that the sensing polymercan be advantageously coated on inner surface of the tip of themicroneedle. The sensing polymer can be prevented from falling as themicroneedle pricks user's skin for sensing.

Accordingly, the present invention provides a sensing device forinterstitial fluid. The sensing device includes a substrate and amicroneedle unit. The microneedle unit at least comprises a firstmicroneedle set used as a working electrode and arranged on thesubstrate in an array, and a second microneedle set used as a referenceelectrode. The second microneedle set comprises at least a microneedle.The first microneedle set comprises at least a sheet having a throughhole on which a barbule forms at the peripheral. One of the sheetsprovides the through hole from which the barbules at the edge of theother sheets go through, and the barbules are disposed separately. Themicroneedle of the present invention has sufficient mechanical strength.The microneedle can be kept intact after the microneedle pricks userskin for sensing. Moreover, the microneedle has simple manufactureprocess, which is beneficial for mass production.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the exploded view of the transdermal microneedlescontinuous monitoring system according to an embodiment of the presentinvention from one viewing direction.

FIG. 2 shows the exploded view of the transdermal microneedlescontinuous monitoring system from another viewing direction.

FIG. 3 shows a schematic exploded view of the microneedle unit accordingto an embodiment of the present invention.

FIG. 4 is a top view of the microneedle set functioning as workingelectrode according to an embodiment of the present invention.

FIG. 5 is a top view of the microneedle set functioning as workingelectrode according to another embodiment of the present invention.

FIG. 6 is a top view of the microneedle set functioning as workingelectrode according to still another embodiment of the presentinvention.

FIG. 7 is a top view of the microneedle set functioning as workingelectrode according to still another embodiment of the presentinvention.

FIG. 8 shows a perspective of an assembled transdermal microneedlescontinuous monitoring system according to an embodiment of the presentinvention.

FIG. 9 shows a sectional of an assembled transdermal microneedlescontinuous monitoring system according to an embodiment of the presentinvention.

FIG. 10 is a partially sectional view of FIG. 9 , where sensing polymeris coated on the barbules.

FIG. 11 is a partially sectional view of FIG. 9 , where sensing polymeris coated on a test strip.

FIG. 12 shows a partially sectional view of an assembled transdermalmicroneedles continuous monitoring system according to anotherembodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The features of the invention believed to be novel are set forth withparticularity in the appended claims. The invention itself, however, maybe best understood by reference to the following detailed description ofthe invention, which describes an exemplary embodiment of the invention,taken in conjunction with the accompanying drawings, in which:

FIG. 1 shows the exploded view of the transdermal microneedlescontinuous monitoring system according to an embodiment of the presentinvention from one viewing direction, and FIG. 2 shows the exploded viewof the transdermal microneedles continuous monitoring system fromanother viewing direction. The transdermal microneedles continuousmonitoring system of the present invention mainly comprises a substrate10, a microneedle unit 20, a flexible pad 30, a signal processing unit41, a power supply unit 43 and a cover 50, where the signal processingunit 41 and the power supply unit 43 are arranged on a circuit board 40.

According to an embodiment of the present invention, the microneedleunit 20 comprises a first microneedle set 22 used as a workingelectrode, a second microneedle set 24 used as a reference electrode,and a third microneedle set 26 used as a counter electrode. The flexiblepad has an opening 32 through which the microneedle unit 20 passes. Themicroneedle unit 20 further comprises electric conducting posts 21, 23,25 to respectively and electrically connect to the contacts 42, 44 and46 on the circuit board 40. The transdermal microneedles continuousmonitoring system of the present invention uses the flexible pad 30 tohave tight fit with the user's muscle during operating thereof.

The signal processing unit 41 electrically connects to the microneedleunit 20 and receives a concentration data of hypodermal target moleculessensed by the microneedle unit 20. The signal processing unit 41generates a sensing signal manifesting the current physiologicalcondition of user after processing the received concentration data. Thepower supply unit 43 provides working power to the transdermalmicroneedles continuous monitoring system of the present invention.

FIG. 3 shows a schematic exploded view of the microneedle unit 20according to an embodiment of the present invention. The firstmicroneedle set 22 comprises a first sheet 222 and a second sheet 224stacked with the first sheet 222. The first sheet 222 has at least onefirst through hole 2222 defined thereon, and a first barbule 2224 atperipheral of the first through hole 2222. The second sheet 224 has atleast one second through hole 2242 defined thereon, and a second barbule2244 at peripheral of the second through hole 2242, where the secondbarbule 2244 penetrates the first through hole 2222 to juxtapose thefirst barbule 2224. The second sheet 224 of the first microneedle set 22comprises barb 2246 at the peripheral thereof and matched with theaperture 102 defined on the substrate 10. According to anotherembodiment, the second sheet 224 of the first microneedle set 22comprises conductive pin 2248 at the peripheral thereof. The conductivepin 2248 can be inserted into a slot 104 defined on the substrate 10 toelectrically connect to the conductive post 21.

Similarly, the second microneedle set 24 comprises a first sheet 242.The first sheet 242 has at least one first through hole 2422 definedthereon, and a first barbule 2424 at peripheral of the first throughhole 2422. The first sheet 242 of the second microneedle set 24comprises barb 2426 at the peripheral thereof and matched with theaperture 102 defined on the substrate 10. According to anotherembodiment, the first sheet 242 of the second microneedle set 24comprises conductive pin 2428 at the peripheral thereof. The conductivepin 2428 can be inserted into a slot 104 defined on the substrate 10 toelectrically connect to the conductive post 23.

Similarly, the third microneedle set 26 also comprises a first sheet262. The first sheet 262 has at least one first through hole 2622defined thereon, and a first barbule 2624 at peripheral of the firstthrough hole 2622. The first sheet 262 of the third microneedle set 26comprises barb 2626 at the peripheral thereof and matched with theaperture 102 defined on the substrate 10. According to anotherembodiment, the first sheet 262 of the third microneedle set 26comprises conductive pin 2628 at the peripheral thereof. The conductivepin 2628 can be inserted into a slot 104 defined on the substrate 10 toelectrically connect to the conductive post 25.

According to an embodiment of the present invention, the firstmicroneedle set 22, the second microneedle set 24, and the thirdmicroneedle set 26 can be made by punching or etching process. Thematerial of the barbules is selected from the group consisting ofstainless steel, nickel, nickel alloy, titanium, titanium alloy, carbonnanotube, and silicon. The surface of the barbules is coated withbiologically compatible metal. The material of the barbules can also beselected from the group consisting of polycarbonate, polymethacrylicacid, polytetrafluoroethylene, and polyester. The surface of thebarbules is also coated with biologically compatible metal. Moreover,the height of the barbules is 300-600 micrometers; the base width of thebarbules is 150-450 micrometers. The separation between tips of thebarbules is 500-3000 micrometers.

With reference to FIGS. 4 to 7 , FIG. 4 is a top view of the microneedleset functioning as working electrode according to an embodiment of thepresent invention. The first microneedle set 22 comprises a first sheet222 and a second sheet 224 stacked with the first sheet 222. The firstsheet 222 has at least one first through hole 2222 defined thereon, anda first barbule 2224 at peripheral of the first through hole 2222. Thesecond sheet 224 has at least one second through hole 2242 definedthereon, and a second barbule 2244 at peripheral of the second throughhole 2242, where the second barbule 2244 penetrates the first throughhole 2222 to juxtapose the first barbule 2224.

FIG. 5 is a top view of the microneedle set functioning as workingelectrode according to another embodiment of the present invention. Thefirst microneedle set 22 comprises a first sheet 222, a second sheet 224and a third sheet 226 stacked with each other. The first sheet 222 hasat least one first through hole 2222 defined thereon, and a firstbarbule 2224 at peripheral of the first through hole 2222. The secondsheet 224 has at least one second through hole 2242 defined thereon, anda second barbule 2244 at peripheral of the second through hole 2242. Thethird sheet 226 has at least one third through hole 2262 definedthereon, and a third barbule 2264 at peripheral of the third throughhole 2262. The second barbule 2244 and the third barbule 2264 penetratesthe first through hole 2222 to juxtapose the first barbule 2224, and thetips of the barbules are in right triangular arrangement from top view.

FIG. 6 is a top view of the microneedle set functioning as workingelectrode according to still another embodiment of the presentinvention. The first microneedle set 22 comprises a first sheet 222, asecond sheet 224 and a third sheet 226 stacked with each other. Thefirst sheet 222 has at least one first through hole 2222 definedthereon, and a first barbule 2224 at peripheral of the first throughhole 2222. The second sheet 224 has at least one second through hole2242 defined thereon, and a second barbule 2244 at peripheral of thesecond through hole 2242. The third sheet 226 has at least one thirdthrough hole 2262 defined thereon, and a third barbule 2264 atperipheral of the third through hole 2262. The second barbule 2244 andthe third barbule 2264 penetrates the first through hole 2222 tojuxtapose the first barbule 2224, and the tips of the barbules are inisosceles triangular arrangement from top view.

FIG. 7 is a top view of the microneedle set functioning as workingelectrode according to still another embodiment of the presentinvention. The first microneedle set 22 comprises a first sheet 222, asecond sheet 224, a third sheet 226 and a fourth sheet 228 stacked witheach other. The first sheet 222 has at least one first through hole 2222defined thereon, and a first barbule 2224 at peripheral of the firstthrough hole 2222. The second sheet 224 has at least one second throughhole 2242 defined thereon, and a second barbule 2244 at peripheral ofthe second through hole 2242. The third sheet 226 has at least one thirdthrough hole 2262 defined thereon, and a third barbule 2264 atperipheral of the third through hole 2262. The fourth sheet 228 has atleast one fourth through hole 2282 defined thereon, and a fourth barbule2284 at peripheral of the fourth through hole 2282. The second barbule2244, the third barbule 2264 and the fourth barbule 228 penetrates thefirst through hole 2222 to juxtapose the first barbule 2224, and thetips of the barbules are in rectangular arrangement from top view.

In the embodiments shown in FIGS. 4 to 7 , the barbule 2224 of the firstmicroneedle set 22 comprises a tip 2221 and a base 2223. The tips ofthose barbules, after the sheets are stacked together, are not at thesame altitudes. Namely, some barbules pass more through holes than otherbarbules. Alternatively, the height of the barbules can be suchdesigned, based on the stacked order of sheets, that the tips of thosebarbules, after the sheets are stacked together, are at the samealtitudes.

FIG. 8 shows a perspective of an assembled transdermal microneedlescontinuous monitoring system according to an embodiment of the presentinvention.

FIG. 9 shows a sectional of an assembled transdermal microneedlescontinuous monitoring system according to an embodiment of the presentinvention. In this shown embodiment, the first microneedle set 22comprises a first sheet 222 and a second sheet 224 stacked with eachother. The first sheet 222 and the second sheet 224 can be assembled bypunching peripherals thereof. The second microneedle set 24 comprisesonly a first sheet 242 and the third microneedle set 26 comprises only afirst sheet 262. The transdermal microneedles continuous monitoringsystem of the present invention uses the flexible pad 30 to have tightfit with the user's muscle during operation thereof.

FIG. 10 is a partially sectional view of FIG. 9 , where sensing polymeris coated on the barbules. More particularly, the sensing polymer iscoated on the inner faces of the barbules, and anti-irritation medicine(medicine preventing skin from irritation) is coated on outer faces ofthe barbules. In this embodiment, the sensing polymer is a moleculeselected from the group consisting of an antibody, an aptamer, asingle-chain variable fragment (ScFv), a carbohydrate, glucose oxidase(GOx), hydroxybutyrate dehydrogenase (HBHD), and a combination thereof.The transdermal microneedles continuous monitoring system havingbarbules coated with the sensing polymer can sense the concentrationdata of hypodermal target molecules and determine the currentphysiological condition of user with the concentration data.

FIG. 11 is a partially sectional view of FIG. 9 , where sensing polymeris coated on a test strip. The embodiment shown in this figure isdifferent with the embodiment of FIG. 10 in that the first microneedleset 22 in this embodiment is used to withdraw interstitial fluid.Therefore, the sensing polymer is coated on a test strip below the firstmicroneedle set 22 instead of coating on the barbules. In thisembodiment, the test strip is arranged between the first microneedle set22 and the substrate 10. The test strip comprises a conductive layer 92and a plurality of test areas 94 on the conductive layer 92. The testareas 94 are coated with sensing polymer and aligned with the throughholes 2222 of the first microneedle set 22. In this embodiment, the testareas 94 are defined by the resin plate 96. Moreover, the firstmicroneedle set 22 is fixed to the test strip by a binding layer 98. Inorder to prevent the sensing polymer and the anti-irritation medicinefrom environment pollution, a protection layer such as anepoxy-polyurethane (Epoxy-PU) film is formed on the surface of thesensing polymer and the anti-irritation medicine.

FIG. 12 shows a partially sectional view of an assembled transdermalmicroneedles continuous monitoring system according to anotherembodiment of the present invention. In this embodiment, the conductivepin 2248 is bent to electrically connect the contact 42 on the circuitboard 40, thus dispensing with the conductive post.

The invention claimed is:
 1. A transdermal microneedles continuousmonitoring system, comprising: a substrate; a microneedle unitcomprising at least a first microneedle set used as a working electrodeand a second microneedle set used as a reference electrode, each of themicroneedle sets comprising at least a microneedle, the firstmicroneedle set comprising at least two sheets, each of the at least twosheets having a through hole defined thereon and a barbule arranged at aperipheral of the corresponding through hole, the through hole on onesheet allowing the corresponding barbules of an other sheet to pass andthe barbules being disposed separately; a test strip arranged betweenthe first microneedle set and the substrate, wherein the test stripcomprises a conductive layer and a plurality of test areas on theconductive layer, and each of the test areas is coated with sensingpolymer and aligned with each of the through holes of the firstmicroneedle set, respectively; a signal processing unit arranged on thesubstrate and electrically connecting to the first microneedle set andthe second microneedle set; and a power supply unit providing workingpower to the transdermal microneedles continuous monitoring system,wherein the at least two sheets comprise a first sheet, a second sheet,a third sheet and a fourth sheet stacked with each other, the firstsheet having at least one first through hole defined thereon and a firstbarbule at a peripheral of the first through hole, the second sheethaving at least one second through hole defined thereon and a secondbarbule at a peripheral of the second through hole, the third sheethaving at least one third through hole defined thereon and a thirdbarbule at a peripheral of the third through hole, the fourth sheethaving at least one fourth through hole defined thereon and a fourthbarbule at a peripheral of the fourth through hole, wherein the secondbarbule, the third barbule and the fourth barbule penetrate the firstthrough hole to juxtapose the first barbule, and tips of the barbulesare in rectangular arrangement.
 2. The transdermal microneedlescontinuous monitoring system in claim 1, wherein the material of thebarbules is selected from the group consisting of stainless steel,nickel, nickel alloy, titanium, titanium alloy, carbon nanotube, andsilicon, and the surface of the barbules is coated with biologicallycompatible metal.
 3. The transdermal microneedles continuous monitoringsystem in claim 1, wherein the material of the barbules is resin, andthe surface of the barbules is coated with biologically compatiblemetal.
 4. The transdermal microneedles continuous monitoring system inclaim 1, wherein each of the barbule of the first microneedle setcomprises a tip and a base, wherein the tips of the barbules of the atleast two sheets are not at the same altitudes after the at least twosheets are stacked and the through hole of one sheet is penetrated bythe barbules of the other sheets.
 5. The transdermal microneedlescontinuous monitoring system in claim 1, wherein each of the barbule ofthe first microneedle set comprises a tip and a base, wherein the tipsof the barbules of the at least two sheets are at the same altitudesafter the at least two sheets are stacked and the through hole of onesheet is penetrated by the barbules of the other sheets.
 6. Thetransdermal microneedles continuous monitoring system in claim 1,wherein the microneedles of the first microneedle set and the secondmicroneedle set are formed by punching or etching.
 7. The transdermalmicroneedles continuous monitoring system in claim 1, wherein each ofthe barbules has a sensing polymer coated on an inner surface thereof.8. The transdermal microneedles continuous monitoring system in claim 7,further comprising a protection layer on the sensing polymer.
 9. Thetransdermal microneedles continuous monitoring system in claim 1,wherein each of the barbules has an anti-irritation medicine coated onan outer surface thereof.
 10. The transdermal microneedles continuousmonitoring system in claim 9, further comprising a protection layer onthe anti-irritation medicine.